The goal is to improve the clinical usefulness of biological markers of cancer (CEA--the prototype) by elucidating their pathophysiology and metabolism. The key role of the liver in regulating circulating glycoproteins and defining mechanisms by which Kupffer and hepatic cells clear them is being investigated. By inhibiting this reversibly, plasma levels will be raised to detectable levels allowing earlier detection and improved monitoring. A CEA-binding protein has been isolated from rat liver Kupffer cells. Studies of the effect of biliary obstruction on CEA levels will elucidate mechanisms and clinical relevance. An assay for measuring asialo-glycoprotein activity in patients' sera has been developed. Naturally occurring inhibitor(s) of Kupffer cell CEA binding have been found in some patients with very high CEA levels and efforts are being made to purify and characterize it. Non-CEA candidate marker(s) for "undifferentiated" cancer are being sought using established colon cancer and other cell lines. Fresh biopsy tissue will be grown in culture and in nude mice. A combination of immunohistopathological and immunochemical procedures characterize the proteins. Monoclonal and polyclonal antibodies to new putative tumor proteins are screened by a battery of malignant tissues and cells in in vitro culture. Clinical and pathological correlates of immunohistochemical staining of pathological tissues and fluids will be studied. A more quantitative analysis of tissue "differentiation" will standardize pathological diagnosis. Comparison with tissue CEA staining and circulating levels thereof will improve clinical usefulness of CEA (and other markers) in managing patients with CEA-\and non-CEA-producing malignancies.